Tryptophan hydroxylase

Tryptophan hydroxylase (TPH) (tryptophan 5-monooxygenase, EC 1.14.16.4) catalyses the reaction between tryptophan, 5,6,7,8-tetrahydrobiopterin (BH4) and O2 to give 5-hydroxytryptophan and 4a-hydroxy-tetrahydrobiopterin. This reaction is the first and rate limiting step in the biosynthesis of serotonin (See scheme).

Together with phenylalanine hydroxylase (EC 1.14.16.1) and tyrosine hydroxylase (EC 1.14.16.2), TPH form the small enzyme family of aromatic amino acid hydroxylases (AAAH). These enzymes all contain iron and use BH4 as a co-substrate in the hydroxylation of their respective aromatic amino acids. Additionally all mammalian AAAH form homotetramers and each monomer consists of three domains. These domains are the N-terminal regulatory domain (100-150 residues), the catalytic domain (approximately 315 residues) and the C-terminal tetramerisation domain (approximately 30-40 residues).

The two isoforms of tryptophan hydroxylase
TPH exists in two isoforms called TPH isoform 1 (TPH1) and TPH isoform 2 (TPH2). The existence of two isoforms was observed when TPH was purified and characterised from different tissues. The gene encoding for rabbit TPH1 was identified in 1987 by Grenett et al. and a few years later the human gene for TPH1 was identified on chromosome 11. The gene for isoform 2 was identified in 2003 by Walther et al. and the human gene is located on chromosome 12. The two isoforms are expressed in different tissues. TPH2 is mainly expressed in serotonergic neurons of the brain and gut. TPH1 is expressed in other parts of the body such as the pineal gland, skin cells , mast cells , intestinal mucosa and enterochromafin cells and in cancer cells. The main difference between the two isoforms is that the N-terminal is extended by 46 residues in TPH2.

3D structures of Tryptophan hydroxylase
3hf8, 3hfb, 3hf6 – hTPH + inhibitor – human

1mlw – hTPH + cofactor

3e2t – TPH catalytic domain + Trp – chicken

Additional Resources
For additional information, see: Amino Acid Synthesis & Metabolism